Search PubMed⌕ Search

Biomedical subjects

R F Kefford

Publications and source records attributed to R F Kefford.

At least 55 records · Page 3Linked to original sources
PubMed1991

Loss of allelic heterozygosity on distal chromosome 1p in Merkel cell carcinoma. A marker of neural crest origins?

The location of genes involved in tumor evolution has been inferred from experiments in which loss of constitutional heterozygosity has been detected in tumor DNA at high frequency in specific chromosome regions. For example, cytogenetic and molecular abnormalities on chromosome 1p have been reported in tumors such as malignant melanoma and neuroblastoma which arise in cells derived from embryonic neural crest tissue. To extend these observations, we have examined tumor DNA from three cases of Merkel cell carcinoma for evidence of loss of constitutional heterozygosity on the short arm of chromosome 1. In all three cases, heterozygous allelic deletions of varying extent on distal chromosome 1p were detected in tumor DNA. Comparisons with neural crest tumors suggest that loss of heterozygosity on distal chromosome 1p in Merkel cell tumors may be a marker of neural crest origin.

Alleles↗
PubMed1991

The WDNM1 gene product is a novel member of the 'four-disulphide core' family of proteins.

It has been previously demonstrated that the WDNM1 gene is downregulated in metastatic rat mammary adenocarcinomas. Detailed analysis of the structure of WDNM1 mRNA reveals the presence of two transcripts generated by alternative splicing of a single exon. The unspliced version possesses an in-frame termination codon which encodes a predicted protein of 18 amino acids. The spliced version encodes a predicted protein of 60 amino acids which exhibits strong homology to a family of proteins possessing a conserved arrangement of cysteine residues. This family includes several proteinase inhibitors suggesting that WDNM1 could encode a product with proteinase inhibiting capacity. Possible modulation in the level of this protein product could be related to overall proteinase activity of specific tumour cells which, in turn, could influence the invasive and metastatic potential of such cell populations.

Adenocarcinoma↗
PubMed1991

Hereditary melanoma in Australia. Variable association with dysplastic nevi and absence of genetic linkage to chromosome 1p.

Hereditary cutaneous malignant melanoma in association with the presence of multiple precursor lesions termed the dysplastic nevus syndrome (DNS) has been reported to display autosomal dominant inheritance with high penetrance. The gene for this disease was recently assigned to the distal short arm of chromosome 1 on chromosomal band 1p36, 7.6 centimorgans distal to the locus for the pronatrodilatin (PND) gene. We assessed 119 family members of eight newly described Australian families, 30 of whom had cutaneous malignant melanoma. Only eight of these affected individuals also had dysplastic nevi (DN). An additional 15 family members had DN alone. Pedigrees fell into three groups: 1) hereditary melanoma alone with no associated DN, 2) hereditary melanoma with occasional DN-affected individuals, and 3) hereditary melanoma with DN. All families displayed an autosomal dominant pattern of inheritance. An analysis of the cosegregation of the cutaneous malignant melanoma/DN trait with eight polymorphic DNA markers on the short arm of chromosome 1, including the distally located DNA markers D1S47 and PND yielded a strongly negative probability of linkage. The putative gene for susceptibility to melanoma in these families was effectively excluded from this region of the short arm of chromosome 1. No evidence for linkage was found at any of the other chromosome 1 markers examined. These findings suggest that hereditary melanoma is heterogeneous in relation to the genetic basis and its association with the DNS.

Adolescent↗
PubMed1991

Synchronous cisplatin infusion during radiotherapy for the treatment of metastatic melanoma.

In two pilot studies, 55 patients with symptomatic metastases from malignant melanoma were treated with irradiation and concurrent cisplatin. In the first group, cisplatin was given as a continuous intravenous infusion of 20 mg/m2 per day on days 1-5 and 22-26, with irradiation on days 2, 5, 9, 16, 23 and 26. The second group received 20 mg cisplatin over 24 h commencing 1 h before each fraction of irradiation on days 1, 4, 8, 11, 15 and 18. The first series of 28 patients had 30 lesions treated. Nine (30%) of these lesions responded completely and 10 (33%) achieved partial response for an overall response rate of 63% (95% confidence interval 44-80%). Survival was not evaluated in this group. The second group was comprised of 27 patients, with one irradiated lesion each. 1 patient achieved a complete response and 13 (48%) a partial response for an overall response rate of 52% (32-71%). Median survival was 21 weeks (16-31 weeks). Treatment was well tolerated with nausea and vomiting being the most common toxicity. Synchronous cisplatin infusion with radiotherapy achieves high response rates in metastatic melanoma. Whether it is superior to radiotherapy alone will require evaluation in a randomised trial.

Adult↗
PubMed1991

Single institutional experience with non-seminomatous germ cell tumours of the testis: local perspectives on a curable cancer.

We have reviewed 77 patients with Non-seminomatous germ cell tumour of the testis (NSGCTT) treated at a single institution. A residual mass following definitive treatment occurred in 16 patients (35%), 13 of whom had a resection of the mass, yielding active tumour in only one patient. Nine patients (12%) relapsed including four of the 14 with Stage I disease who were treated by orchidectomy alone. Four relapses occurred at more than two and a half years after primary treatment. Relapse prior to the development of clinical symptoms or signs was evident in three of nine patients; in two patients by routine imaging and one with elevated routine serum markers. Three of the nine patients who relapsed had elevated serum markers. Two patients died from disease but there were four treatment-related deaths (7%). Overall, 64 patients (83%) remain disease free at the time of follow-up. A further seven (9%) have been lost to follow-up but were disease-free at a minimum of 26 months after diagnosis. This study confirms features of this disease including the excellent prognosis when adequately treated. However, it also reveals the problems of late or marker negative relapses, the implementation of an observation policy in Stage I disease and treatment related mortality in young men.

Adolescent↗
PubMed1990

Molecular oncogenetics of metastasis.

Metastasis is a complex non-stochastic process that is most likely the result of genetic and epigenetic interactions of a wide variety of genes. The search for a single gene which can encompass such a pleiotropic response as to account for the observed phenotypic characteristics of metastatic tumour populations has been unsuccessful. Particular studies involving gene transfection, subtractive hybridisation and cell fusion are beginning to identify specific genes which contribute to metastasis in some cell types. However, such analyses are complicated by the inherent genetic instability and phenotypic heterogeneity present in tumour populations. A more detailed understanding of the metastatic process may require an abandoning of current generalised approaches to metastasis in favour of concentrating on key components of the metastatic cascade such as adhesion and invasion.

Adenovirus Early Proteins↗
PubMed1990

Lack of correlation between immunoglobulin and T cell receptor gene rearrangements and TdT expression in acute myeloid leukaemia.

Thirty-two cases of acute myeloid leukaemia (AML) were examined for expression of terminal deoxynucleotidyl transferase (TdT) and rearrangements of the genes coding for the immunoglobulin heavy chain and the beta chain of the T cell receptor, in order to establish whether these two forms of lineage infidelity are linked. In 17 cases of AML with greater than or equal to 10% TdT+ cells, three cases showed evidence of gene rearrangement, two having clonal rearrangements in the immunoglobulin gene and one with a rearranged T cell receptor gene. Among 15 AML cases without significant numbers of TdT-positive blasts, three cases had rearrangements in both immunoglobulin and T cell receptor genes, while a fourth case had an immunoglobulin gene rearrangement. No relationship was seen between lymphoid gene rearrangements and expression of the lymphoid surface antigens CD7 and CD10. The lack of association between TdT expression and gene rearrangements does not support the concept of an orderly activation of the recombinase machinery in those cases of AML with features of early lymphoid differentiation.

Adolescent↗
PubMed1990

Demonstration of somatic rearrangements and genomic heterogeneity in human ovarian cancer by DNA fingerprinting.

A detailed study was performed in 14 patients with epithelial ovarian tumours using the satellite probes 33.15, 228S and 216S to investigate the nature of somatic changes and frequency with which clonal changes could be demonstrated during metastasis and progression. Somatic changes were evident in approximately 70% of ovarian tumours, the most common being a deletion or reduction in intensity of a band suggesting loss of heterozygosity. Additional changes that were observed included increased intensification of single bands and the appearance of novel DNA fragments. Somatic alterations were seen following digestion of DNA with methylation resistant restriction endonucleases indicating that methylation differences alone could not account for all of the somatic changes. Using DNA fingerprint analysis ovarian tumours were shown to be heterogeneous with different DNA patterns observed in different sites in five of eight patients. Generally, within an individual patient the primary and metastases appeared to share a DNA fingerprint pattern with minor variations occurring in different sites suggesting that different populations have derived from a common stem line. This study clearly demonstrates that DNA fingerprint analysis is a sensitive method to detect somatic changes in tumour DNA and for investigating the development of clonal heterogeneity in ovarian tumours.

Adenocarcinoma↗
PubMed1989

Transcriptional down-regulation of a rat gene, WDNM2, in metastatic DMBA-8 cells.

We have investigated differences in gene expression between a metastatic and nonmetastatic clone of the DMBA-8 rat mammary adenocarcinoma cell line and have previously identified a differentially expressed gene WDNM1 (T.N. Dear, I.A. Ramshaw, and R.F. Kefford, Cancer Res., 48: 5203-5209, 1988). To further investigate differences in mRNA expression between these cell lines, a complementary DNA library from the nonmetastatic cell line was probed with labeled complementary DNA enriched for sequences specific to this line. We report here the identification in nonmetastatic cells of a second gene, WDNM2, which encodes a 1.7-kilobase mRNA corresponding to a protein (Mr 28,000-30,000) the expression of which shows a positive correlation with the nonmetastatic phenotype in three independently derived rat mammary adenocarcinoma cell lines and is regulated transcriptionally. Homologous sequences in the human genome have been identified. The function of this new gene may relate to regulation of the metastatic phenotype in this tumor.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Amplification of c-ras-Ki oncogene in human ovarian tumours.

Amplification of the c-ras-Ki oncogene has been the most consistent finding reported in studies on oncogene activation in ovarian cancer, but for the most part the studies have been small and the results conflicting. In order to determine whether amplification occurred de novo in primary tumours or was associated with tumour progression and metastasis, 81 tumour samples from different sites in 26 patients with ovarian tumours and 7 xenografted ovarian tumour cell lines were assayed. Amplification of c-ras-Ki occurred infrequently and was apparent in a single metastatic site in a patient with poorly differentiated serous cystadenocarcinoma of the ovary. Ten-fold amplification of the c-ras-Ki oncogene was also evident in a benign ovarian fibroma. Amplification of the c-ras-Ki oncogene is rare in ovarian tumours and does not appear to play a fundamental role in tumor development or progression.

Blotting, Southern↗
PubMed1989

Loss of alleles from the distal short arm of chromosome 1 occurs late in melanoma tumor progression.

The gene for familial malignant melanoma and its precursor lesion, the dysplastic nevus, has been assigned to a region of the distal short arm of chromosome 1, which is frequently involved in karyotypic abnormalities in melanoma cells. We have examined loci on chromosome 1p for loss-of-constitutional heterozygosity in 35 melanomas and 21 melanoma cell lines to analyze the role of these abnormalities in melanocyte transformation. Loss-of-heterozygosity at loci on chromosome 1p was identified in 15/35 (43%) melanomas and 11/21 (52%) melanoma cell lines. Analysis of multiple metastases derived from the same patient and of melanoma and lymphoblastoid samples from a family with hereditary melanoma showed that the loss-of-heterozygosity at loci on distal 1p is a late event in tumor progression, rather than the second mutation that would occur if melanoma were due to a cellular recessive mechanism. Comparisons with neuroblastoma and multiple endocrine neoplasia (MEN2) suggest that the frequent 1p loss-of-heterozygosity in these malignancies is a common late event of neuroectodermal tumor progression.

Alleles↗
PubMed1989

Phorbol esters potentiate the induction of class I HLA expression by interferon alpha.

We have studied the effect of phorbol esters on the induction of class I histocompatibility antigen (HLA) expression by interferons (IFNs) in the T-cell line MOLT-4 and in the MOLT-4 mutant YHHH. Addition of IFN-alpha to phorbol 12,13-dibutyrate-pretreated MOLT-4 cells causes a greater than 20-fold increase in the expression of class I HLA, as compared to a 4- to 7-fold IFN-alpha-induced increase in control cells. Pretreatment with phorbol 12,13-dibutyrate does not alter the class I HLA response to IFN-gamma or the responses of other IFN-induced genes. This effect of phorbol 12,13-dibutyrate reproduces in MOLT-4 cells the phenotype of the mutant YHHH, which also displays a selective enhanced class I HLA response to IFN-alpha. Pretreatment of YHHH with phorbol 12,13-dibutyrate does not affect any of the responses induced by IFN. These findings suggest the existence of a phorbol ester-sensitive factor, inducible in MOLT-4 and constitutively expressed or modified in YHHH, which operates in the pathway of induction of class I HLA by IFN-alpha but not in the pathway used by IFN-gamma.

Drug Synergism↗
PubMed1989

Method of extracting DNA from fine needle aspirates of human solid tumors for Southern blot analysis.

A rapid, simple, convenient method for extracting DNA from fine needle aspiration (FNA) samples of human solid tumors for Southern blot hybridization studies is described. After the preparation of an air-dried cytologic smear, the remaining sample in the needle was rinsed directly into a test tube for DNA extraction. The extraction procedure, in which manipulation of the sample is minimized, produced sufficient DNA for Southern blot analysis within 24 hours of the FNA biopsy in the ten consecutive cases studied. The DNA bound to the nylon membranes can be washed and reexamined with a variety of probes, allowing studies of lymphoid cell lineage, oncogene amplification or tumor progression. The assessment of cellularity on the cytologic specimen at the time of FNA provided a reliable guide to the need for further passes to obtain sufficient cells for DNA hybridization; the cytologic diagnosis could also be made on the smears.

Adenocarcinoma↗
PubMed1989

Empiric single agent or combination antibiotic therapy for febrile episodes in neutropenic patients: an overview.

Febrile episodes during chemotherapy-induced neutropenia are a frequent cause of morbidity and mortality in cancer patients. Empiric antibiotic therapy commencing at the onset of fever is selected according to three principles: intravenous therapy is used to rapidly achieve bactericidal serum levels, antibiotics with appropriate antibacterial spectra are required, and combinations of antibiotics have been preferred for their synergistic activity. Initial empiric monotherapy with single antibiotics such as imipenem which have a sufficiently broad antibacterial spectrum in their own right are potentially as efficacious as conventional combination therapies. Granulocytopenic periods complicated by fever are significantly longer in patients receiving chemotherapy for leukaemia than in patients undergoing treatment for lymphoma and solid tumours. However, defervescence of fever following commencement of antibiotic therapy occurs equally rapidly in these three groups. The persistent granulocytopenia leaves leukaemic patients at greatest risk of breakthrough or second infections. These patients therefore appear to be the most likely to benefit from the clinical use of haemopoietic growth factors such as granulocyte and granulocyte-macrophage colony-stimulating factor.

Agranulocytosis↗
PubMed1988

Differential expression of a novel gene, WDNM1, in nonmetastatic rat mammary adenocarcinoma cells.

Subtractive hybridization was used to investigate differences in gene expression between a metastatic clone and nonmetastatic clone of the rat mammary adenocarcinoma line DMBA-8 which differ 100-fold in their metastatic behavior. Several differentially expressed highly homologous mRNAs (600 to 900 base pairs) were identified from the nonmetastatic line which are expressed at a level 20-fold higher than in the metastatic clone. Available sequence data show no homology to published gene sequences. There is no difference between the metastatic and nonmetastatic clones regarding DNA restriction fragment sizes or copy number of the gene. Expression of this newly described gene, named WDNM1, may be an important correlate of nonmetastasis in this tumor model.

9,10-Dimethyl-1,2-benzanthracene↗